In the last several years, significant progress has been made in understanding the relevance of the adaptive T cell immune response to the clearance of the Gram-negative pathogen Salmonella typhimurium. Studies in our laboratory established that CD8 + T cells are essential elements in the protective immune response against infection with S. typhimurium, and these studies led to the identification of peptide epitopes recognized by bacteria-specific CD8 effector T cells. In this revised competitive renewal, we will build on these initial observations and develop a model system where infection is initiated by the natural oral route of infection. This mode will allow us to define the essential cellular elements of the mucosal immune system that respond to also enable us to understand the contribution of innate cellular immunity to the clearance of infection. In the next five years, we will focus our efforts on the following Aims: Aim 1. What are the characteristics of the novel CD8 ix/13 expressing Intraepithelial Lymphocytes (IELs) that are induced in the small intestine after oral infection with S. typhimurium? Specifically, we will determine the activation state, TCR usage, recognition properties and functional capacity of these T cell subsets. Aim 2. Do NK and NKT cells contribute to the development of a protective T cell-mediated immune response to S. typhimurium ?. Aim 3. Do bacteria, that display defined differences in cellular tropism (e.g., dendritic cells vs. epithelial cells), vary in their ability to stimulate both innate and adaptive host immune responses? The studies contained in this proposal are designed to address the various host immune elements that contribute to the clearance of infection and the generation of protective immunity to a model Gram-negative pathogen Salmonella typhimurium. We hope to apply this in formation to the design of vaccine strategies that will evoke potent protective immunity as well as contribute to understanding the etiological link between infection with gram-negative pathogens in the development of autoimmune disease. Given that many of the cellular receptors in the mouse model have human counterparts, we argue that this murine model will yield valuable information that may be applied to the human setting.